1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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Three similarly designed 6-month placebo-controlled trials form the basis of the
approval of exenatide for use in patients with DM2 who exhibit unacceptable glycemic
control while on metformin and/or a sulfonylurea testing the addition of exenatide to
metformin alone, sulfonylurea alone, or metformin and a sulfonylurea together (166-168).
The placebo-adjusted decline of HbA1c from baseline levels of 8.2 – 8.6% was ~1.0% in
each trial. A mean placebo-adjusted weight loss of 2.5 kg occurred when exenatide was
added to metformin, 1.0 kg when the drug was added to a sulfonylurea, and 0.9 kg when it
was added to metformin plus a sulfonylurea. All patients began the treatment with 5 ug
injected twice daily subcutaneously, before the morning and evening meals, for the first
month, followed by 10 ug twice daily thereafter (166-168.) Following the 30- week,
majority of the patients continued in an open-labeled extension for 82 weeks.
A subset of 73 subjects from the exenatide + metformin and exenatide + metformin +
sulfonylurea groups had post-prandial beta-cell function evaluated at baseline and after 6
months (201). Glucose excursions after meal tolerance tests were significantly reduced after
exenatide but not after placebo. To assess beta-cell function independent of confounding
effects from post-prandial plasma glucose differences, mathematical modeling was
performed incorporating 3 main components of beta-cell function: rate sensitivity (early
insulin secretion rate [ISR]), dose- response relating ISR to plasma glucose concentration
(glucose sensitivity) and a potentiation factor, which is a function of time and may reflect
the actions of non-glucose secretagogues along with other factors (202). The mathematical
model indicated a greater insulin response for any glucose concentration. Also, exenatide
increased potentiation at 2-hour post meal compared with placebo, presumably due to its
incretin effect since it is only partially affected while the beta-cell function is inherently
impaired in DM 2 (203). In summary, exenatide enhanced post-prandial beta-cell function
in patients with DM2 treated with metformin or metformin and sulfonylurea.
It was demonstrated that intravenous exenatide enhanced first and second phase insulin
secretion in response to an IV glucose bolus in subjects with DM2 treated with
diet/exercise, metformin or acarbose and compared to healthy subjects with normal OGTT
not receiving exenatide. Exenatide-treated patients with DM2 had a similar secretory
pattern (first- and second-phase insulin secretion) but higher insulin levels than healthy
subjects in contrast to patients with DM2 treated with placebo who had blunted first phase